Precision Medicine Doctoral Training Programme

A massive attack on how messenger RNA sequence specifies condition-dependent RNA fate

Precision Medicine Project - A massive attack on how messenger RNA sequence specifies condition-dependent RNA fate

Supervisor(s): Dr Edward Wallace, Dr Vicent Pelechano [Karolinska Institute], Prof Guido Sanguinetti, Prof Chris French  
Centre/Institute: Institute for Cell Biology

Background: All organisms must respond to changes in their environment. Fungi detect and adapt to stressful environmental changes by reorganizing their messenger RNA (mRNA) and protein. There are thousands of mRNAs in each cell and a huge variety of environmental conditions, begging the question of which signals drive specific mRNA processing changes in which conditions, and why? Modern sequencing methods now measure these aspects of cellular regulation in unprecedented breadth and depth. Modern synthetic biology makes it possible to test hundreds of mechanistic hypotheses in a single experiment, as long as we can design the experiments well, and then organize and analyze the data!

Aims: This project will integrate transcriptomics, bioinformatics, and synthetic biology to understand the mechanistic basis of stress-dependent gene expression regulation in the model fungus, Saccharomyces cerevisiae. You will computationally analyze gene expression data to identify regulatory signals, for example sequence motifs in the untranslated regions of mRNAs. You will perform a massively parallel reporter assay: make libraries of chimeric mRNAs to test combinations of different regulatory signals, and measure the effect of these regulatory signals on mRNA production, processing, and decay. The ideal outcome would be a quantitative systems-level model of how sequence signals interact to regulate mRNA fate across environmental conditions. These insights can then be applied to regulation in other organisms,  including important fungal pathogens, and to human genetic diseases.

Training outcomes: This project will develop your skills in quantitative biology, computation, and experimental design and execution. You will learn to deal with a variety of data sources including ‘omics data, and apply statistics and data analysis methods to rigorously separate biological signals from background noise. In the lab, you will learn how to use automation to perform large experiments that substantially advance our understanding of cellular regulation. You will work towards “digital excellence”, so that your entire workflow is as reproducible as possible, from experiments through multiple analysis steps, equipping you for success in tackling other large-scale projects in the future.

Supervisors: This project will be jointly supervised by Dr. Edward Wallace at the University of Edinburgh (https://ewallace.github.io/) and Dr. Vicent Pelechano at the Karolinska Institute (http://pelechanolab.com/). Dr. Wallace studies how fungi dynamically reorganize their RNA and protein to adapt to environmental change, and recently discovered a role of RNA and protein relocalization in regulating responses to heat stress (Wallace 2015). Dr. Pelechano studies transcriptome regulation, and has developed new sequencing methods including TIF-seq, that revealed the surprising extent of variation in transcript start and end sites (Pelechano 2013). The project will receive input from Prof. Guido Sanguinetti on computational biology aspects, and Prof. Chris French on synthetic biology.

References:

1. Wallace EWJ, et al. 2015. Reversible, Specific, Active Aggregates of Endogenous Proteins Assemble upon Heat Stress. Cell 162: 1286–1298.

2. Pelechano V, Wei W, Steinmetz LM. 2013. Extensive transcriptional heterogeneity revealed by isoform profiling. Nature 497: 127–131.

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  • The deadline for 19/20 applications is 5pm on Monday 7th January 2019.
  • Please note all applications for the Precision Medicine DTP should be submitted to the University of Edinburgh, even those applying for a project at the University of Glasgow.
  • Applicants must apply to a specific project, ensure you include details of the project you are applying to in Section 4 of your application. You must contact the primary supervisor prior to making your application.  
  • As you are applying to a specific project, you are not required to submit a Research Proposal as part of your application. 
  • Please ensure you upload as many of the requested documents as possible at the time of submitting your application.